Clinical hyperthyroidism as a result of benign hyperplasia of the thyroid is a very common condition in old cats (Feldman and Nelson, 1996) and is stated as being the most common endocrine disorder in cats (Buijtels et al., 2006).
The average age of cats with hyperthyroidism is twelve to thirteen years. The most common phenomenon with hyperthyroidism is an increase of weight loss, in spite of greater appetite.
Cats with hyperthyroidism can be treated in three different ways. These are:                1) Destruction of the hyper functioning gland tissue by the administration of radioactive iodine;        2) Surgical removal of the abnormal gland tissue (thyroidectomy);        3) Treatment with medication inhibitors of the synthesis of gland hormone (antihyperthyroid drugs).        
Surgery has traditionally been the main treatment, but has a significant incidence of unwanted effects, and does not deal with the 9% of cats with ectopic thyroid tissue (Naan et al., 2006). Radioactive iodine is probably the treatment of choice as it has been shown to prolong survival time (Milner et al., 2006), but has all the drawbacks involved in handling radioactive substances safely.
This makes pharmaceutical treatment an attractive option (Trepanier, 2006) however, antihyperthyroid drugs must be administered for life, one to three times per day. This may be difficult as cats in particular are notoriously hard to dose with oral drugs such as tablets or even liquids.
Because of this, many compounding pharmacies around the world have started formulating drugs into gels which are applied to the inner side of the ear of the cat which aim to be absorbed through the skin for systemic action.
Not all drugs are suitable for transdermal penetration and only a few have been studied to determine whether they reach therapeutic levels after absorption by this route. The drug needs to be highly lipophilic and formulated in the correct vehicle for transdermal absorption (Riviere et al., 2001).
Methimazole has been used to treat hyperthyroidism in cats in the USA in tablet form. Due to difficulties with pharmacokinetics, the tablet needs to be administered repeatedly.
Carbimazole is a more lipid soluble prodrug of methimazole and is used in tablets to treat hyperthyroidism in cats in New Zealand. Neither carbimazole or methimazole are registered for use in animals in New Zealand, but veterinarians are able to prescribe them for treatment of hyperthyroidism under veterinary discretionary use of human medicines.
Methimazole has been used in a transdermal preparation of pluronic lecithin organogel (PLO). However transdermal absorption was poor in pharmacokinetic studies but it did show clinical efficacy in some cats with repeated applications (Lecuyer et al., 2006; Sartor et al., 2004; Hoffmann et al., 2003, 2002). This clinical efficacy may be due to repeated application of the gel on the same site, which could have resulted in irritation of the skin and enhanced drug absorption through the breached skin barrier. Substantial skin irritation after application of PLO for several days has been reported. Another possible explanation of the clinical effects is that they are due to oral ingestion of the PLO during grooming (Murdan, 2005).
It was also reported (Lecuyer et al, 2006) that a third of the owners of cats in their study noted a non-homogenous texture develop in the PLO gel caused by drug precipitation. It was thought this could cause a variation in drug concentration between doses.
A transdermal carbimazole formulation has recently been shown to reduce tT4 concentrations in cats (Buijtels et al., 2006). The formulation used for delivery of carbimazole is described as being eye ointment solution and lecithin. It is the inventors finding that eye ointments are made to not be absorbed directly, rather they are used to transfer the active agent from the ointment into the tear ducts. In the present invention, the inventors have found that it is desirable to not only deliver the active agent transdermally, but also to deliver the whole formulation transdermally to ensure complete absorption and full efficacy. The inventors have also found that use of lecithin is undesirable, as lecithin tends to give the formulation a thick gel texture which is sticky to handle and also does not have good absorption characteristics.
Further, as noted in Buijtels et al, it is difficult to select a penetration enhancer for a given permient. Penetration enhancer potencies tend to be drug specific or at least only predictable for a series of permients with similar physio-chemical properties. Therefore, the findings in Buijtels et al should not be seen as indicative that all transdermal formulations will provide similar efficacy.
In view of the above several patents are now discussed.
U.S. Pat. Nos. 5,871,950 and 5,556,754 describe the use of methimazole to suppress expression of MHC Class 1 molecules in the treatment of autoimmune diseases. Column 18, lines 28-32 (U.S. Pat. No. 5,871,950) and column 18, lines 50-54 (U.S. Pat. No. 5,556,754) state that “The MHC class 1 suppressing drugs (of which methimazole is included as one example) may be administered as a sterile pharmaceutical composition further comprising a biological carrier including, but not limited to saline, buffer, dextrose, ethanol and water”. Ethanol is described but there is no suggestion or teaching that the ethanol acts as a penetration enhancer. Ethanol and the other biological carriers listed are commonly used in injectable compositions and that is the implied use in these patents. Further, U.S. Pat. Nos. 5,871,950 and 5,556,754 state that the MHC class 1 suppressing drugs may be administered by “topical application”, however there is no further teaching of a means by which this could be accomplished. As noted above, penetration enhancer potencies tend to be drug specific or at least only predictable for a series of permients with similar physio-chemical properties and therefore the teachings of U.S. Pat. Nos. 5,871,950 and 5,556,754 are vague if at all on specifics formulations to achieve the objective of a formulation for transdermal delivery of an antihyperthyroidism drug.
US 2005/0209295 describes the use of methimazole and derivatives for inhibition and prevention of cell adhesion and cell adhesion mediated pathologies. The specification teaches that the compounds may be formulated into pharmaceutical compositions that may be administered topically (among other routes). The specification goes on to state that “topically-transdermal patches may be used”, and in paragraph 36 goes on to list possible pharmaceutical carriers. However there are no examples of transdermal formulations or any data that the drugs can actually be carried over the dermal barrier.
US 2006/0240087, US 2003/0170195, US 2006/0233870 and US 2002/0058068 describe transdermal administration of a drug by administration of a composition comprising a blend of two or more acrylic-based polymers having differing functionalities so as to modulate the drug solubility and hence the delivery rate. The specifications, list methimazole as a preferred drug for use in the invention, however the previous paragraphs also contains lists of drugs the authors reference the Merck index as “suitable for dermal administration”. The specifications go on to give an extensive list of “penetration enhancers” for use in the inventions. However, only a limited number of those compounds listed are shown to be effective in the examples and there are no examples using methimazole or any other antihyperthyroid drug. As noted above, penetration enhancer potencies tend to be drug specific or at least only predictable for a series of permients with similar physio-chemical properties and hence without examples the compounds taught in US 2006/0240087, US 2003/0170195, US 2006/0233870 and US 2002/0058068 can only be seen as mere speculation.
To summarize, since alternative treatment for hyperthyroidism is either potentially dangerous to the cat (surgery) or to its handlers (radioactive iodine), a formulation of an antihyperthyroid drug which can be administered in a stress-free way would be a major benefit to small animal practice.
It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice.
All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country.
It is acknowledged that the term ‘comprise’ may, under varying jurisdictions, be attributed with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term ‘comprise’ shall have an inclusive meaning—i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. This rationale will also be used when the term ‘comprised’ or ‘comprising’ is used in relation to one or more steps in a method or process.
Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.